The laboratory mouse is widely used as animal model in pre-clinical cancer research and drug development. Acquiring actual anatomy of a laboratory animal, such as a mouse, is frequently needed for localizing and quantifying functional changes. Currently in vivo imaging of mouse anatomy is achieved with PET, SPECT, and optical imaging modalities or tomographic imaging systems such as micro-CT and micro-MR as imaged with modalities. Also, anatomical imaging is used to measure organ morphometry, quantify phenotypical changes and build anatomical models. In preclinical small animal studies, in vivo estimation of the mouse anatomy is also important to aid in localizing functional changes and measuring organ morphometry. Some molecular imaging modalities also need complimentary anatomical information to help with image acquisition, reconstruction and analysis, such as micro-SPECT scan-planning optical tomography reconstruction, micro-PET attenuation correction and tissue uptake quantification.
Currently, anatomical context is provided with tomographic x-ray CT systems that are either directly attached to the functional imaging system, or have a co-registered field of view and use specialized imaging chambers. In vivo imaging of the mouse anatomy using small animal tomographic imaging systems, such as micro computed tomography (micro-CT) and micro magnetic resonance imaging (micro-MR) systems can provide 3D tomographic images with micron-level resolution (≦100 μm for in vivo imaging of both modalities). Multiple approaches have been developed to delineate organ regions from micro-CT and micro-MR images based on image segmentation or atlas registration. However, these systems present expensive infrastructure, operation and maintenance costs which greatly diminish their dissemination potential.
An important limitation of current in vivo micro-CT technology is the low soft tissue contrast. Due to a tradeoff between acquisition time, radiation dose and image quality, standard imaging protocols of in vivo micro-CT scans normally use low-dose X-rays and a limited number of projections, resulting in low soft tissue contrast. Although contrast agents for soft tissues can be applied, the use of contrast agents increases study cost and complexity. Therefore, most pre-clinical studies still use non-contrast enhanced micro-CT images, and segmentation of soft organs from non-contrast micro-CT images remains problematic. It is therefore desirable to develop an approach to enable the estimation of 3 dimensional internal mouse anatomy from low-cost non-tomographic imaging systems.
Several mouse atlas registration approaches have been proposed for micro-CT images (Baiker M, Milles J, Dijkstra J, Henning T D, Weber A W, Que I, Kaijzel E L, Lowik C W, Reiber J H, Lelieveldt B P. Atlas-based whole-body segmentation of mice from low-contrast micro-ct data. Med Image Anal; 14(6): 723-37) and micro-MR images (Kovacevic N, Hamarneh G, Henkelman M. Medical image computing and computer-assisted intervention-miccai 2003, pp. 870-877, 2003). Other methods address mouse atlas registration with low-cost hardware such as surface laser-scanners (Joshi A A, Chaudhari A J, Li C, Dutta J, Cherry S R, Shattuck D W, Toga A W, Leahy R M. Digiwarp: A method for deformable mouse atlas warping to surface topographic data. Phys Med Biol; 55(20): 6197-214) and optical cameras (Baiker M, Vastenhouw B, Branderhorst W, Reiber J H C, Beekman F, Lelieveldt B P F. Atlas-driven scan planning for high-resolution micro-spect data acquisition based on multi-view photographs: A pilot study. Proceedings of Medical Imaging 2009: Visualization, Image-Guided Procedures, and Modeling, Lake Buena Vista, Fla., USA, 2009. SPIE.; Wildeman M H, Baiker M, Reiber J H C, Lowik C W G M, Reinders M J T, Lelieveldt B P F. 2d/3d registration of micro-ct data to multi-view photographs based on a 3d distance map. Proceedings of Biomedical Imaging: From Nano to Macro, 2009. ISBI '09. IEEE International Symposium on, 2009). However, these methods are either computationally expensive or semi-automatic, therefore not suitable for high-throughput applications. Further, use of micro-CT and micro-MR technologies in combination with these systems is also complicated. To avoid these problems, some researchers have turned to the use of low-cost non-tomographic imaging systems, such as optical cameras, 3D surface scanners and bench-top planar X-ray systems. Optical cameras can be used to obtain 2D body profiles which can be useful in inter-modality co-registration, respiratory motion monitoring, and 3D surface geometry reconstruction. Recent developments in 3D surface scanning techniques make it possible to build a surface scanner with consumer-market electronic devices (e.g. laser pointer, digital camera and/or pocket projector). As a result, several research prototypes and commercial products have been developed, such as the laser scanner with conical mirror and the structured light-based surface scanner. Bench-top planar X-ray systems are more expensive than optical cameras and surface scanners, but are still far less costly than fully 3D tomographic systems. With a planar X-ray projection, the anatomy of some internal structures (e.g. bones and lungs) can be readily observed. Several commercial small animal optical imaging systems have integrated planar X-ray systems as anatomical references, such as the KODAK In-Vivo Multispectral System FX and the Caliper LifeSciences IVIS® lumina XR system.
Besides laser scanners and optical cameras, a bench-top projection X-ray system can be another low-cost choice. However, no methods have used bench-top X-ray systems for mouse atlas registration. To address these requirements we have developed a fully-automatic atlas registration method dedicated to a low-cost hardware design. Preferably, the desired method combines different low-cost imaging modalities such as bench-top X-rays and optical cameras to give better estimations of the 3 dimensional organ anatomy.
Several software approaches have also been developed to register a digital mouse atlas with the non-tomographic modalities, in order to approximate 3D organ anatomy. Baiker et al. registered the mouse atlas to optical profiles of the mouse body to assist scan-planning of region-focused micro-SPECT (Baiker M, Vastenhouw B, Branderhorst W, et al. (2009) Atlas-driven scan planning for high-resolution micro-SPECT data acquisition based on multi-view photographs: a pilot study. Proc SPIE Medical Imaging; Visualization, Image-Guided Procedures, and Modeling (Lake Buena Vista, Fla., USA) 72611L-72618). Khmelinskii performed mouse atlas registrations under the guidance of multi-view optical photos (Khmelinskii A, Baiker M, Kaijzel E L, et al. (2010) Articulated whole-body atlases for small animal image analysis: construction and applications. Mol. Imag. Biol.). Zhang et al. aligned the mouse atlas with body surface reconstructed from multiple-view photos, aiming to assist fluorescence tomographic reconstruction (Zhang X, Badea C T and Johnson G A (2009) Three-dimensional reconstruction in free-space whole-body fluorescence tomography of mice using optically reconstructed surface and atlas anatomy. J Biomed Opt 14: 064010). Joshi et al. developed a Finite-Element-Model-based atlas warping method to register the atlas with laser scans of the mouse surface (Joshi A A, Chaudhari A J, Li C, et al. (2010) DigiWarp: a method for deformable mouse atlas warping to surface topographic data. Phys. Med. Biol. 55: 6197-6214). Chaudhari et al. proposed a method for registering a mouse atlas to a surface mesh acquired by a structured light scanner (Chaudhari A J, Joshi A A, Darvas F and Leahy R M (2007) A method for atlas-based volumetric registration with surface constraints for Optical Bioluminescence Tomography in small animal imaging. Proc SPIE Medical Imaging 2007: Physics of Medical Imaging 6510: 651024-651010). However, based on a review of the literature, current methods mainly focus on registration with optical modalities like optical photos and surface scans, and no method has been reported for mouse atlas registration with X-ray projections.